Abstract Tuberculosis (TB) claims the lives of 4,000 individuals every day as the leading cause of death due to infectious disease. In those with human immunodeficiency virus (HIV) infection, however, the risk for TB treatment failure or post-therapy relapse is greatly increased. TB relapse is strongly associated with development of drug resistance and occurs through poorly understood effects of HIV on host immunity. Understanding the HIV factors driving TB relapse, then, represents an important gap in knowledge needed for development of interventions that support immune containment and complement drug therapy. We describe the first animal model of HIV- mediated TB relapse following drug treatment, using the humanized mouse. Our preliminary data suggests that defects in activation of IL-17 pathways due to HIV infection are a potential mechanism for loss of immunity to the causative agent of TB, Mycobacterium tuberculosis (Mtb). Based on these findings, we hypothesize that Th17 T cells play an important role in containment of paucibacillary TB following drug therapy that is compromised by HIV infection. Our collaborative group previously conducted investigations of T cell immune defects in HIV+ and HIV- human subjects in Nairobi, Kenya, who had recently completed the intensive phase of TB chemotherapy. We propose to expand our investigations to now demonstrate how HIV status effects Th17 cell memory function following TB chemotherapy in virally suppressed and non-suppressed people. We propose to further use our humanized mouse model of HIV-mediated TB relapse to identify the mechanistic role of Th17 cells and IL-17 in TB containment, and demonstrate how activation of Th17 cells during the immune response to Mtb promotes virus propagation in the lung. We propose the following specific aims: 1) Aim 1, Poor recovery or dysfunction of the Th17 compartment predicts post-chemotherapy TB relapse in human subjects with HIV; and 2) Aim 2, HIV co-infection perturbs protective function of Th17/IL-17 as a mechanism for driving Mtb relapse following TB drug therapy in co-infected humanized mice. We expect these results to inform efforts to target the IL-17 cytokine family in development of preventive measures to reduce TB recurrence in those at risk due to HIV co-infection.